Kinomics platform using GBM tissue identifies BTK as being associated with higher patient survival

Better understanding of GBM signalling networks in-vivo would help develop more physiologically relevant ex-vivo models to support therapeutic discovery. A 'func-tional proteomics' screen was undertaken to measure the specific activity of a set of protein kinases in a two-step cell-free biochemical assay to define dominant kinase activities to identify potentially novel drug targets that may have been over-looked in studies interrogating GBM-derived cell lines. A dominant kinase activity derived from the tumour tissue, but not patient-derived GBM stem-like cell lines, was Bruton Tyrosine Kinase (BTK). We demonstrate that BTK is ex-pressed in more than one cell type within GBM tissue; SOX2-positive cells, CD163-positive cells, CD68-positive cells and an unidentified cell population which is SOX2-neg-ative CD163-negative and/or CD68-negative. The data provide a strategy to better mimic GBM tissue ex-vivo by reconstituting more physiologically heterogeneous cell co-culture models including BTK-positive/negative cancer and immune cells. These data also have implications for the design and/or interpretation of emerging clinical trials using BTK inhibitors because BTK expression within GBM tissue was linked to longer patient survival.